11H-isoquino[4,3-c]cinnolin-12-ones: novel anticancer agents with potent topoisomerase I-targeting activity and cytotoxicity

• Published in: Bioorganic & medicinal chemistry Vol. 12; no. 4; pp. 795 - 806
• Main Authors: RUCHELMAN, Alexander L, SINGH, Sudhir K, RAY, Abhijit, XIAOHUA WU, YANG, Jin-Ming, NAI ZHOU, LIU, Angela, LIU, Leroy F, LAVOIE, Edmond J
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Science 15.02.2004
• Subjects: Animals; Antineoplastic agents; Antineoplastic Agents - chemical synthesis; Antineoplastic Agents - chemistry; Antineoplastic Agents - pharmacology; Antineoplastic Agents - toxicity; Biological and medical sciences; Cell Line; DNA - genetics; DNA - metabolism; DNA Topoisomerases, Type I - metabolism; Female; General aspects; Heterocyclic Compounds, 2-Ring - chemical synthesis; Heterocyclic Compounds, 2-Ring - chemistry; Heterocyclic Compounds, 2-Ring - toxicity; Humans; Inhibitory Concentration 50; Medical sciences; Mice; Mice, Nude; Molecular Structure; Neoplasm Transplantation; Pharmacology. Drug treatments; Topoisomerase I Inhibitors; Topotecan - pharmacology; Antineoplastic agent; Pentacyclic compound; Intraperitoneal administration; Nitrogen heterocycle; Lactam; Cytotoxicity; Isomerases; Structure activity relation; Aromatic compound; Mammary gland; Chemical synthesis; Tumor cell; Oxygen nitrogen heterocycle; Human; Enzyme; Rodentia; DNA topoisomerase; Oral administration; Enzyme inhibitor; Tetracyclic compound; Malignant tumor; In vitro; In vivo; Vertebrata; Chemotherapy; Mammalia; Cell line; Treatment; Mouse; Animal
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2003.10.061

Recent studies have identified 2,3-dimethoxy-8,9-methylenedioxy-11-[(2-dimethylamino)ethyl]-11H-isoquino[4,3-c]cinnolin-12-one (1a) as a novel topoisomerase I-targeting agent with potent cytotoxic activity. The effect of varied substituents at the 11-position of 2,3-dimethoxy-8,9-methylenedioxy-11H-isoquino[4,3-c]cinnolin-12-ones on topoisomerase I-targeting activity and cytotoxicity was evaluated. Potent TOP1-targeting activity was observed when the 11-position was substituted with either a 2-(N,N-dimethylamino)ethyl, a 2-(N,N-diethylamino)ethyl, a n-butyl, or a 2-(pyrrolidin-1-yl)ethyl group. The addition of a beta-methyl group to 1a provided an analogue with dramatically reduced TOP1-targeting activity and cytotoxicity. Analogues of 1a wherein the 2-(N,N-dimethylamino)ethyl group was replaced with a (2-tetrahydrofuranyl)methyl, a 2-(piperidin-1-yl)ethyl, or a 2-(4-methylpiperazin-1-yl)ethyl substituent exhibited decreased activity as TOP1-targeting agents. Replacement of the dimethoxy groups of 1a with hydrogen atoms resulted in an analogue with significantly decreased TOP1-targeting activity and cytotoxicity. Removal of both the vicinal dimethoxyl groups and the methylenedioxy moiety resulted in a complete loss of TOP1-targeting activity. The presence of a 9-nitro substituent in place of the 8,9-methylenedioxy group of 1a resulted in a decrease in relative TOP1-targeting activity and cytotoxicity. Compounds 1a and the 11-n-butyl analogue 1d were evaluated for antitumor activity in the human tumor xenograft model using athymic nude mice. The non-estrogen responsive breast tumor cell line MDA-MB-435 was used in these assays. At dose levels that approached its maximum tolerated dose, 1a proved to be effective in inhibiting tumor growth in vivo when administered orally or by ip injection.